Methyl and i,g-dimethyl-ergoline i
derivatives



United States Patent 463/62 16 Claims. (Cl. 260-2855) Our inventionrelates to 6-methyland 1,6-dimethylergoline I derivatives, which areuseful as pharmacologically active substances and as intermediates forthe synthesis of other products having therapeutic uses, and to aprocess for their preparation.

The new compounds, which are an object of our invention, are 6-methyland1,6-dimethyl-ergoline I derivatives having the following structuralformula:

,H ,NHR" Xis O,N0H' or \NHR H R" is H, or Ac, and Ac is the acyl radicalof an aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylicacid having from 1 to 10 carbon atoms in the radical.

As far as known, compounds of 6-methyland 1,6-dimethyl-ergoline I and11, having a side chain of two or more carbon atoms in the 8-position,have not previously been described.

The process of the invention is essentially in four stages although someof the compounds of the invention result from only some of these stages.The process, as illustrated by the following scheme, comprises reacting6-methyl- (or 1,6-dimethyl-)-8-carboxarnido-(alkylated or not at theamide nitrogen atom)-ergoline I (A) with an alkyl-magnesinm halide toafford the corresponding ketone (B) which is thereafter converted intothe oxime (C) by reaction with hydroxylamine. By reducing said oxime (C)with sodium or potassium in a lower aliphatic alcohol, the correspondingcrude 8-(a-amino-alkyl)-6- methyl- (or l,6-dimethyl)-ergoline I (D) isobtained, which consists of two stereoisomers at the 17-carbon atomwhich may be chromatographically separated. The two stereoisomers,respectively called Rectus and Sinister according ot the convention ofIngold, Cahn and Prelog (Experientia 12, 1956, page 81), may be acylatedat the 17-amino group. In the following reaction scheme R, R and Ac havethe significance given above and Y represents two hydrogen atoms oralkyl groups or one of each.

N-CH3 Grignard H lo f a gen R R R I I (I) O C=N-OH N-CHa NCH3 I oximaton reduction N H2011 Na alcohol I I R R R H R H N112 NH-Ac 5 N-CHaaeylation reduction Na alcohol Series "Reetus" (DH-NH: j N-CHschromatographic separation P IJ R NH1 R NH-Ac N-CHa NCH aeylatmn l I a aR R Series Sinister" 6-methyland 1,6-dimethyl-S-carboxamido-ergoline I,the starting materials for the process of the invention, may be ineither D or L form or a racemic mixture. symbol I which follows the nameof the ergoline derivatives indicates that the hydrogen atom in the10-position has the oc-COnfigllfatiOIl.

The starting materials (A), dissolved or suspended in an anhydrousorganic solvent, such as an aromatic hydrocarbon or ether, e.g. benzeneor tetrahydrofuran, are reacted in the warm, preferably at the boilingtemperature of the solvent employed, with an excess of Grignard reagent,preferably methyl-magnesium or ethylmagnesium bromide or iodide for aperiod from 10 to 30 hours, preferably 20 hours, to yield thecorresponding ketone (B). The ketone (B) is isolated from the reactionmixture and purified by crystallization or by chromatography. It hasbeen found that the best results are obtained by employing an excess ofGrignard reagent of 10-15 equivalents with respect to the startingmaterial.

The ketone (B) thus obtained is treated with an excess (4-6 equivalents)of hydroxylamine in a lower aliphatic alcohol, such as ethanol, in thewarm, preferably under reflux, and the corresponding oxime (C) isisolated and purified in the known manner.

The reduction of said oxime to the corresponding amine (D) is carriedout with a reducing agent which is able to reduce the ketoximic groupinto the amino group, preferably sodium or potassium in a loweraliphatic alcohol such as methanol or ethanol. The reduction may becarried out at room temperature, but is preferably completed in thewarm. I

The 8-(u-amino-alkyl)-6-methyl (or 1,6-dimethyl)- ergoline I thusobtained is a mixture of two stereoisomer forms at -17, respectivelyindicated with R and S (Rectus and Sinister). The two forms may beseparated by chromatography and crystallization, as they show aremarkable difierence of migration velocity on elution. Eachstereoisomer of the R or S form may be acylated in known manner with theanhydride or the chloride of an aliphatic, cycloaliphatic, aromatic andheterocyclic carboxylic acid having from 1 to 10 carbon atoms, in theoptimal presence of tertiary amines such as pyridine, homologues thereofand dimethylaniline. The acylation may be carried out also on themixture of the two stereoisomers R and S and the two stereoisomer acylderivatives then separated by chromatography. Typical examples of acylderivates, prepared according to the invention, are those of thefollowing acids: acetic, propionic, butyric, valerianic, hexanoic,heptanoic, octanoic, decanoic, cyclopentanecarboxylic,cyclopentylpropionic, succinic, benzoic, 2,6-dimethoxy-benzoic,3,4,5-trimethoxybenzoic, phenyl-propionic, phenoxyacetic,m-phenoxy-propionic, ethylcarbamic, nicotinic and their analogues.

The products of the invention are crystalline, colorless oryellow-colored solids, soluble in usual organic solvents and in acids.

The products of the invention show a good pharmacological activity andare particularly useful as oxytocic, antienteraminic, adrenolytic,hypotensive and sedative drugs.

The following examples are intended to illustrate, but not to limit theinvention:

7 EXAMPLE 1 8-acetyl-6-m'ethyl-erg0line I A solution of methylmagnesiumbromide (prepared from 12 g. of metallic magnesium) is added dropwise toa boiling suspension of 12 g. of dihydrolysergamide I, prepared by themethod of Stoll and Hofmann (Helv. Chim. Acta, 1946, 29, pages 635), in1200 cc. of anhydrous tetrahydrofuran. The reaction mixture is refluxedfor 20 hours. After having decomposed the magnesium'complex with an icecooled solution of am- The taining 12 g. of hydroxylamine.

monium chloride and having separated the organic layer, the motherliquors are extracted with benzene. The extracts are dried overanhydrous sodium sulphate and concentrated in vacuo. A foamy residue,weighing 11.60 g. is obtained. The residue is then taken up with benzeneand chromatographed over neutral alumina to yield 3.30 g. of8-acetyl-6-methyl-ergoline I which melts at 204- 206 C.; [a] -:870(c.=0.3 in pyridine).

EXAMPLE 2 8-acetyl-o-methyl-ergoline l I 20 g. of diethylamide ofdihydrolysergic acid I, prepared by the method of Stoll and Hofmann(Helv. Chim. Acta, 1955, 38, page 421), dissolved in 600 cc. ofanhydrous benzene, are poured into 600 cc. of a boiling solution ofmethylmagnesium bromide in benzene, prepared from 20 g. of metallicmagnesium. The mixture is kept at boiling point for 20 hours. Afterdecomposing the magnesium complex with an aqueous solution of ammoniumchloride, separating the organic layer and extracting the mother liquorswith benzene, the extracts are dried over anhydrous sodium sulphate andconcentrated in vacuo. The residue is taken up with cc. of warm ;ether,and 8-acetyl-6-methyl-ergoline I crystallizes out.

10.19 g. are obtained, melting at 204-206 C.;

(c.=0.28 in pyridine).

The mother liquors chromatographed over neutral alumina give a further1.170 g. of product, melting at 203-205 C.

EXAMPLE 3 8-acetyl-1,6-dimethyl-erg0line 1 Into 700 cc. of a boilingsolution of methylmagnesium bromide in benzene (prepared from 24 g.magnesium) there are poured 24 g. of diethylamide ofl-methyl-dihydrolysergic acid I, prepared by the method of Troxler andHofmann (Helv. Chim. Acta, 1957, 40, page 1721), dissolved in 700 cc. ofanhydrous benzene. The reaction mixture is refluxed for 20 hours. Afterdecomposing the magnesium complex with an aqueous solution of ammoniumchloride and separating the benzene layer, the moter liquors are furtherextracted with benzene, the combined extracts are dried over anhydroussodium sulphate and are concentrated in vacuo. The residue is taken upwith benzene and chromatographed over neutral alumina to give 11.41 g.of 8-acetyl-1,6-dimethyl-ergoline I melting at 97-100 C.; [a] =-87(c.=0.38 in pyridine).

' EXAMPLE 4 Oxime of 8-acetyl-6-mefhyl-ergoline I8-acetyl-6-methyl-ergoline I oxime is obtained by warming, on a waterbath for 10 minutes, a solution of 10 g. of 8-acetyl-6-methyl-ergoline Iin 650 cc. of ethanol con- The reaction mixture is thereafter kept atroom temperature for two days. 9.63 g. of oxime are obtained, which uponrecrystallization from ethanol melts at 252-254 C.; [a] '=-115 (c.=0.21in pyridine).

EXAMPLE 5 Oxime of 8-acetyl-1,6-dimethyl-erg0line I 4 g. of'8-acetyl-l,6-dimethyl-ergoline I are dissolved in 280 cc.-of ethanolcontaining 5 g. of hydroxylamine, refluxed for 10 minutes, and kept atroom temperature for two days. 3.42 g. of oxime of8-acetyl-1,6-dimethylergoline I are obtained, melting at 247-249" C.;

EXAMPLE 6 (17 R) and (17 S)-8-(zx-amino-ethyl)-6-methyl-erg0line l 8 g.of metallic sodium are gradually added during about 2 hours to asolution of 2 g. of oxime of 8-acetyl- 6-methyl-erg0line I in 80 cc. ofboiling absolute ethanol. After the addition is completed, the reactionmixture is diluted with 40 cc. of boiling absolute ethanol and 4 g. ofmetallic sodium are added during 1 hour. The mixture is then kept warmuntil the sodium is completely dissolved. The mixture is then cooled toabout 50 C., and the sodium ethylate is almost completely neutralizedwith 25% aqueous acetic acid. The amine, extracted with chloroform, iswashed with a dilute solution of sodium bicarbonate and then with water.The solution is concentrated in vacuo and a foamy brown residue,weighing 1.92 g., is obtained. This product consists of a mixture of twostereoisomers with stereoisomerism at the 17-carbon atom. The two formsmay be separated by chromatography and crystallization because they showa remarkable diiference of migration velocity in the elution. Thechromatographic separation is performed over an activated magnesiumsilicate, such as Florisil, with chloroform-ethyl ether as eluent.

The two stereoisomeric forms have been assigned their configurationafter chemico-physical investigations. According to the convention ofIngold, Cahn and Prelog (Experientia 12, 1956, page 81) theconfiguration R (=Rectus) has been given to the most mobile amine,melting at 223-225 C.; [a] 135 (c.=0.27 in pyr idine), and theconfiguration S (=Sinister) to the less mobile amine, melting at 226229C.; [u] =-l39 (c.=0.3 in pyridine). The structural formulae are as Theweight ratio of the two amines is about 60% of amine R to 40% of amineS.

EXAMPLE 7 (17 R) and (17 S)-8-(a-amin0-ethyl)-1,6-dimethylergoline I To2 g. of oxime of 8-acetyl-1,6-dimethyl-ergoline I, prepared as describedin Example 5, dissolved in 80 cc. of boiling ethanol, 8 g. of metallicsodium are added during about 2 hours. When the addition is over, afurther 40 cc. of ethanol are added and the whole kept boiling while afurther 4 g. of metallic sodium are added during about 1 hour. At theend of the addition, the mixture is refluxed until the sodiumdisappears. The reaction mixture is cooled and the pH is adjusted toabout 8 with 25% aqueous acetic acid. The amine is extracted withchloroform and the extract is washed with sodium bicarbonate solution,dried and finally evaporated to dryness in vacuo. 1.98 g. of an oilyorange residue is obtained. By carrying out the chromatographicseparation by the same technique as described in Example 6, two amines 6(17 R) and (17 S) having the following structural formulae are obtained:

EXAMPLE 8 (J 7 R) -8-(a-acetyl-amino-ethyl)-=6-methyl-ergoline l Asolution of 0.35 g. of (17 R)-8-(a-amino-ethyl)-6- methyl-ergoline I,dissolved in 2.5 cc. of anhydrous pyridine, is cooled to about -10 C.and 0.25 cc. of acetyl chloride are added. The reaction mixture is keptat this temperature for 20 minutes and then at room temperature for afurther 20 minutes. The mixture, diluted with chloroform and a smallamount of methanol, is washed with aqueous sodium hydroxide solution,with sodium bicarbonate solution and finally with water. Afterdistilling oil the solvent in vacuo, the residue is crystallized fromacetone-petroleum ether. 0.27 g. of (17R)-8-(u-acetylamino-ethyl)-6-methyl-ergoline I, melting at 25 6257 C.are obtained; [a] -44 (c.=0.27 in pyridine).

EXAMPLE 9 (17 S) -8-(a-aCetylamin0-ethyl) -6-methyl-ergolin=e I Byoperating in the same way as in Example 8, from 0.35 g. of (17S)-8-(u-amino-ethyl)-6-methyl-ergoline I in 2.5 cc. anhydrous pyridineand 0.25 cc. of acetyl chloride, and by recrystallization fromacetone-petroleum ether, 0.24 g. of (17S)-8-(a-acetylamino-ethyl)-6-methylergoline I, melting at 176 C. areobtained;

(c. =0.23 in pyridine).

EXAMPLE 10 (17 R) and (J7 S)-8-(a-acetylamino-ethyl-6- methyl-ergoline IBy operating in the same way as in Example 8, from 1 g. of a mixture of17 R and 17 S amine, prepared as described in Example 6, in 7 cc. ofanhydrous pyridine and 0.7 cc. of acetyl chloride, and afterchromatography of the crude product over neutral alumina and elutionwith ghloroform-benzene, two acetyl derivatives are ob tame 17 R)-8-(a-acetylamino-ethyl) -6-methyl-ergoline I; melting point 256257 C.;[m] =44 (c.=0.27 in pyridine);

(17 S) -8-(u-acetylamino-ethyl)-6-methyl-ergoline I; melting point175176 0.; [a] =-116 (c.=0.23 in pyridine).

EXAMPLE 11 (1 7 R) -8- a-benzoylamino-ethyl) -6-methyl-ergoline I Byoperating in the same way as in Example 8, from 0.35 g. of (17R)-8-(a-amino-ethyl)-6-methyl-ergoline I in 2.5 cc. of anhydrouspyridine and 0.7 cc. of benzoyl chloride, and by recrystallization frombenzene-petroleum ether, 0.21 g. of (17 R)-8-(m-benzoylamino-ethyl)-6-methyl-ergoline I are obtained; melting point 138-140" C.; [a] =153(c.=0.28 in pyridine).

EXAMPLE 12 (17 S)-8-(a-benzoylamino-ethyl)-6-methyl-erg0line I Byoperating in the same way as in Example 8, from 0.350 g. of (17S)-8-(a-amino-ethyl)-6-methyl-ergoline I in 2.5 cc. of anhydrouspyridine and 0.7 cc. of benzoyl chloride, and by crystallization frombenzene-petroleum ether, 0.190 g. of 17 S)-8-a-benzoy1amino-ethyl) 6-methyl-ergoline I are obtained, melting at 149'150 C.;

[a] =40 (c.=0.23 in pyridine).

EXAMPLE 13 (17 R)-8-(a-eth0xycarbamid0-ethyl) -6-methylerg0line I Thepreparation is carried out as in Example 8, from 0.350 g. of (17 R)-8-(x-amino-ethyl)-6-methyl-ergoline I in 2.5 cc. of anhydrous pyridine and0.25 cc. of ethyl chlorocarbonate, and by crystallization frombenzenepetroleum ether, 0.190 g. of (17 R)-8-(a-ethoxycarbamido-ethyl)-6-methyl-ergoline I are obtained, melting at 87-91 C.with decomposition; [u] "=81 (c.=0.3% in pyridine).

EXAMPLE 14 (17 R) and (17 S)-8-(a-acetylamin0)-1,6-dimethylergoline I1.980 g. of 8-(a-amino-ethyl)-1,6-dimethyl-ergoline I, dissolved in 15cc. of anhydrous pyridine, are cooled to about l0 C. and 1.5 cc. ofacetyl chloride are added. The reaction mixture is kept at thistemperature for minutes and then at room temperature for a further 20minutes. The mixture is diluted with chloroform and a small amount ofmethanol, is then washed with an aqueous solution of sodium hydroxide, asolution of sodium bicarbonate and finally with water. The solvent isremoved in vacuo and a foamy residue is obtained, which is taken up withbenzene and chromatographed over neutral alumina and then eluted withchloroformbenzene. By crystallizing the two eluates, respectively (17R)-8-(a-acetylamino-ethyD-1,6-diInethyl-ergoline I, melting at 224-226C., [a] =52 (c.:=0.29 in pyridine), and (17 S)-8-(a-acetyl-amino-ethyl)-l,6-dimethy1-ergoline I, melting at 247249 C.,[a] =104 (c. =0.38 in pyridine), are obtained.

EXAMPLE is 8-(a-amz'n0-pr0pyl)-6-methyl-(and 1,6-dimethyl)- ergoline Iderivatives The preparation of these derivatives, which are the higherhomologues of 8-(a-amino-ethyl)'-6-methyl (or 1,6- dimethyl)-ergoline Iderivatives, is carried out by reacting dihydrolysergamide or1-methyl-dihydrolysergamide or their N-alkyl derivatives at the amidenitrogen with ethylmagnesium bromide, instead of methyl-magnesium bro- 119 9 and then as in the appropriate previous example.

8 We claim: 1. A compound of the formula:

$I i NOHs Z I R wherein:

R is selected from the group consisting of H and CH R is selected fromthe group consisting of CH and C H X is selected from the groupconsisting of O, NOH, a

N HR

,NHR" E R" is selected from the group consisting of hydrogen and an acylgroup of (a) substituted and unsubstituted saturated aliphatic acid withup to 3 carbon atoms, wherein the substituent is selected from the groupconsisting of phenyl and phenoxy; (b) substituted and unsubstitutedbenzoic acid, wherein the substituent is methoxy; and (c) nicotinicacid.

References Cited by the Examiner I Burger: Medicinal Chemistry, pages585-6 and 622 (1960).

Stoll: Chemical Reviews, volume 47, pages 197-218, (1950).

NICHOLAS S. RIZZO, Primary Examiner.

1. A COMPOUND OF THE FORMULA: